Recent data from our program demonstrate that the level of HIV DNA within peripheral blood mononuclear cells (PBMC HIV DNA) is a strong marker of cognitive impairment in patients who are naive to HAART, patients on chronic HAART, and among patients with undetectable plasma HIV RNA. Based on preliminary data, PBMC HIV DNA likely represents the degree of HIV infection in circulating monocytes rather than lymphocytes. Since activated cells of the monocyte/macrophage lineage play a pivotal role in the pathogenesis of HIV-associated Dementia (HAD), HIV DNA may be an important neuropathogenic marker. New data presented in this application reveal that pre-HAART HIV DNA level predicts 12-month post-HAART cognitive function. We also present evidence that HIV DNA may increase monocyte chemotaxis by elevating MCP-1 secretion from monocytes, a finding that would be expected to increase transmigration of monocytes to the brain. The potential significance of these findings becomes more apparent in the context of incomplete cognitive recovery after HAART. Incomplete cognitive recovery could be an active or passive (permanent brain damage) process. A major gap in our current knowledge relates to a lack of biological marker of this incomplete recovery. Developing our hypotheses is likely to advance this area of science and bridge this gap in our knowledge-base. We propose to define the long-term dynamic relationship between the inability of HAART to eradicate HIV DNA in the peripheral monocyte reservoir and cognitive performance among patients initiating HAART for the first time in Bangkok, Thailand. We will define the clinical correlate with neuropsychological testing and evaluate mechanisms by determining the extent to which HIV DNA contributes to monocyte activation in peripheral blood and glial activation by MR spectroscopy and by CSF markers of immune activation while ensuring that the primary effects of HIV DNA are not due to increased HIV RNA in CSF. PUBLIC HEALTH RELEVANCE This proposal will study whether high levels of HIV infected monocytes (a type of cell in the bloodstream) that persist in HIV-infected individuals who receive good antiretroviral therapy against HIV explain why dementia does not completely resolve following such therapy. Understanding why this happens will allow us to find better ways to prevent or treat this devastating complication of HIV.